Summary

Rocuronium is an aminosteroid neuromuscular-blocking agent (NMBA) that facilitates the induction of paralysis during surgery. Among different NMBAs used, rocuronium is majorly implicated in hypersensitive reactions. The main route of exposure to rocuronium is parenteral via intravenous injection. Obesity is one of the risk factors for rocuronium-induced allergy. NMBAs are known to be the most frequent cause of perioperative anaphylaxis, with rocuronium having the greatest incidence reported. The initial clinical features of rocuronium-induced anaphylaxis include bronchospasm and hypotension. The diagnostic methods used for rocuronium allergy are skin testing, specific IgE measurement, and basophil activation test. Rocuronium IgE has been found to cross-react with succinylcholine, vecuronium, and pancuronium due to similarities in their molecular structures.

Epidemiology

Worldwide distribution

Hypersensitive reactions elicited by NMBAs often become serious and life-threatening. Perioperative anaphylaxis, although a rare occurrence, is a serious event that can often lead to cardiorespiratory failure and mortality. NMBAs are the most frequent cause of perioperative anaphylaxis, with rocuronium having the greatest incidence reported.

A UK-based multi-center, retrospective study on 161 patients with suspected perioperative anaphylaxis during general anesthesia detected that NMBAs (38%, 61/161) were the leading cause of anaphylaxis, and among the different NMBAs used, rocuronium-triggered anaphylaxis occurred in 25% (15/61) cases.

The incidence of anaphylaxis caused by rocuronium globally is not yet clearly known. Moreover, whether the incidence of anaphylaxis is higher with rocuronium than with other NMBAs is a matter of debate. Studies from France, and Australia showed that occurrence of anaphylaxis is higher with rocuronium (about 43-56% of cases) as compared to other NMBAs like vecuronium and succinylcholine (ranging between 11-22%). In contrast there are studies from the USA which were unable to show any difference between rocuronium and vecuronium in terms of anaphylaxis occurrence. Moreover, a 7-year retrospective review in New Zealand on the incidence of intraoperative anaphylaxis caused by NMBAs reported the incidence of anaphylaxis for rocuronium was 1 in 2,499 and this was about 10 times more than that for atracurium (1 in 22,451). Similarly, 6th National Audit project on 266 reports of Grades 3-5 anaphylaxis in a year in UK hospitals found that 25% (64/266) of anaphylaxis was caused by NMBAs. Among the NMBAs, rocuronium was implicated in 42% (27/64) cases with an incidence of 1 in 17,002.

A 12-year survey conducted in France with 1624 cases of severe perioperative anaphylactic reactions caused by NMBAs reported that rocuronium was responsible for IgE-mediated severe anaphylaxis in 42% (680/1624) of cases.

An epidemiologic study in Japan with 55 suspected cases of anaphylaxis (Grade 2 or above) following general anesthesia (total number of cases= 218,936) identified rocuronium as the top causative agent of perioperative anaphylaxis with an incidence of 0.005% (10/ 210,852).

A retrospective review over 5 years conducted in Singapore with 35,361 pediatric cases found 15 cases of perioperative anaphylaxis of grade 2 and above and among them, 5 was IgE-mediated, of which one was rocuronium-induced.

A study was conducted in Lebanon to evaluate drug hypersensitivity reactions (DHR) in 758 adult patients and among them, 90 patients (11.9%) had ambulatory DHR and simultaneous DHR. Out of these 90 patients, 57 were positive for NMBAs and 80% (46/57) of these patients were positive for rocuronium.

Risk factors

Obesity (particularly basal metabolic index> 29.9 kg/) and pholcodine consumption are found to be the risk factors for anaphylaxis caused by NMBA, such as rocuronium.

Route Of Exposure

Main

Rocuronium is administered intravenously to induce paralysis during surgery.

Clinical Relevance

Anaphylaxis is a rapid, severe, and life-threatening hypersensitive reaction, which is often caused by NMBAs. Rocuronium is the leading cause of perioperative anaphylaxis among other NMBAs. Anaphylactic reactions are usually immediate reactions occurring within a few minutes (3-20 minutes with a median of 6 minutes) of NMBA administration in hypersensitive patients as observed in a retrospective study.

Anaphylaxis

A study involving 266 adult cases of perioperative anaphylaxis reported hypotension (46%), bronchospasm (18%), and tachycardia (9.8%) as the initial clinical features of anaphylaxis. Additionally, in patients with rocuronium-induced grades 3-5 anaphylaxis, both bronchospasm and hypotension were equally (nearly 40%) reported as the initial features.

The role of rocuronium in inducing anaphylaxis has been reported in several case reports.

Diagnostics

It is important to identify the agent responsible for perioperative anaphylaxis to prevent serious consequences. A standard method used for detection is the allergy skin tests, although the predictability of skin tests is still questionable. Skin testing is known to lack absolute sensitivity and specificity and the test is required to be performed 4-6 weeks after anaphylaxis to avoid a possible immune refractory period.

Besides skin tests, specific IgE can provide additional information on perioperative anaphylaxis and hence can be considered to detect hypersensitivity of the patients towards any anesthetic agents in case emergency surgery is required. A combined morphine and pholcodine specific IgE assays detected NMBA allergy in an increased number of skin test-positive patients than either test alone in a study. The sensitivity and specificity of these combined specific IgE assays regarding detection of all NMBA skin test positive patients were found to be 71.5% and 94.2% (cutoff threshold: 0.35 kUA/l) respectively and for aminosteroid skin test positive patients were 82.1% and 94.2% respectively.

Basophil activation test (BAT) can be useful as aid in diagnosing NMBA-induced anaphylaxis. A study on 120 patients with 61 patients showing NMBA-induced anaphylaxis and of them, 78.3% (48/61) were rocuronium-positive, found BAT assay to be useful for diagnosis of anaphylaxis in addition to standard assays. A mean BAT sensitivity of 73% and specificity of 78% were obtained.

Prevention And Therapy

Avoidance

Rocuronium should be avoided in cases where patients have a history of IgE-mediated anaphylaxis and appropriate alternative agents should be used instead. Even though it is recommended to avoid agents with positive skin prick test (SPT) results, it is important to consider the risk associated with false negative SPT results.

Cross-Reactivity

Cross-reactivity among NMBAs is common due to the presence of ubiquitous IgE epitopes. About 60%-70% of patients with NMBA allergy show cross-reactivity and is more commonly observed in NMBAs belonging to the aminosteroid group (e.g. rocuronium, pancuronium, vecuronium) than those belonging to the benzylisoquinoline group (e.g atracurium, cisatracurium, mivacurium, doxacurium), see references in.

A 4-year study conducted on 119 patients with perioperative reaction, where an IgE mediated reaction was established in 76 cases, found that 47 patients developed perioperative anaphylaxis due to different NMBAs. The cross-reactivity rate of rocuronium was 22.3%, which was less than that of vecuronium (47.6%). Another study conducted on 80 patients with NMBA-induced anaphylaxis reported that patients with NMBA anaphylaxis were mostly cross-reactive to succinylcholine (>45%), followed by rocuronium (about 32%).

A retrospective study on patients with perioperative anaphylaxis found 21 patients with allergic anaphylaxis due to NMBA, and of them, one patient positive for succinylcholine allergy cross-reacted with rocuronium. Moreover, positive SPT to succinylcholine, vecuronium, and pancuronium was observed in three patients with rocuronium-induced anaphylaxis.

Cross-reactivity of rocuronium with vecuronium and pancuronium was detected in another retrospective analysis of cases from the French pharmacovigilance database with 680 confirmed cases of NMBA-induced anaphylaxis. Cross-reactivity was found in 31 out of 55 cases of rocuronium-attributed anaphylaxis with 61.3% (19/31) showing cross-reactivity to vecuronium, 48.4% to suxamethonium (15/31), and 35.5% to pancuronium (11/31).

Rocuronium and cis-atracurium cross-reactivity and co-sensitization have also been reported. A study on 758 patients with 90 patients showing drug hypersensitivity reactions (DHR) found that rocuronium and cisatracurium were cross-reactive most frequently. Of 57 patients with hypersensitivity to NMBAs, 15 was co-sensitized to 2 molecules and of them, 10 were co-sensitized to rocuronium and cisatracurium.

Explained Results

Allergen information.

Rocuronium is an amino steroidal neuromuscular-blocking agent (NMBA) commonly used to induce paralysis. It can cause both IgE-mediated and non-IgE-mediated hypersensitive reactions.

Clinical information.

Among NMBAs, rocuronium is found to be the leading cause of anaphylaxis in perioperative settings. Bronchospasm and hypotension were equally reported as the initial features.

Cross-reactivity.

IgE cross-reactivity among various NMBAs has been observed in about 60%-70% of patients with NMBA allergy, see references in. Rocuronium cross-reactivity was found mainly with vecuronium (61.3%) suxamethonium (48.4%) and pancuronium (35.5%).

Author: Turacoz

Reviewer: Dr. Ulrica Olsson

Antunes, J., A. M. Kochuyt and J. L. Ceuppens (2014). "Perioperative allergic reactions: experience in a Flemish referral centre." Allergol Immunopathol (Madr) 42: 348-354.

Anzenbacherova, E., A. Spicakova, L. Jourova, J. Ulrichova, M. Adamus, P. Bachleda and P. Anzenbacher (2015). "Interaction of rocuronium with human liver cytochromes P450." J Pharmacol Sci 127: 190-195.

Beyaz, S., R. Coskun, N. Oztop, E. Aygun, M. O. Sungur, T. O. Seyhan, S. Demir, M. Olgac, D. Unal, B. Colakoglu, S. Buyukozturk and A. Gelincik (2022). "Evaluation of skin test indications for general anesthetics in real life: a prospective cohort study." Braz J Anesthesiol 72: 350-358.

Bhananker, S. M., J. T. O'Donnell, J. R. Salemi and M. J. Bishop (2005). "The risk of anaphylactic reactions to rocuronium in the United States is comparable to that of vecuronium: an analysis of food and drug administration reporting of adverse events." Anesth Analg 101: 819-822.

Capuano, A., M. G. Sullo, C. Rafaniello, L. Sportiello, P. Fusco, M. De Vizia and F. Ferraro (2015). "Complete resistance after maximal dose of rocuronium." J Pharmacol Pharmacother 6: 175-178.

Dagher, J., D. Antonios, S. Chollet-Martin, L. de Chaisemartin, M. Pallardy, H. Azouri and C. Irani (2024). "Drug-induced hypersensitivity reactions in a Lebanese outpatient population: A decade-long retrospective analysis (2012-2021)." J Allergy Clin Immunol Glob 3: 100169.

Di Leo, E., P. Delle Donne, G. F. Calogiuri, L. Macchia and E. Nettis (2018). "Focus on the agents most frequently responsible for perioperative anaphylaxis." Clin Mol Allergy 16: 16.

Harper, N. J. N., T. M. Cook, T. Garcez, L. Farmer, K. Floss, S. Marinho, H. Torevell, A. Warner, K. Ferguson, J. Hitchman, W. Egner, H. Kemp, M. Thomas, D. N. Lucas, S. Nasser, S. Karanam, K. L. Kong, S. Farooque, M. Bellamy and N. McGuire (2018). "Anaesthesia, surgery, and life-threatening allergic reactions: epidemiology and clinical features of perioperative anaphylaxis in the 6th National Audit Project (NAP6)." Br J Anaesth 121: 159-171.

Kim, Y. Y., I. T. Kim, S. I. Shin and S. M. Yim (2018). "Intradermal skin tests for rocuronium and cisatracurium in patients with a history of allergy: a retrospective study." Korean J Anesthesiol 71: 296-299.

Krishna, M. T., M. York, T. Chin, G. Gnanakumaran, J. Heslegrave, C. Derbridge, A. Huissoon, L. Diwakar, E. Eren, R. J. Crossman, N. Khan and A. P. Williams (2014). "Multi-centre retrospective analysis of anaphylaxis during general anaesthesia in the United Kingdom: aetiology and diagnostic performance of acute serum tryptase." Clin Exp Immunol 178: 399-404.

Li, J., O. G. Best, M. A. Rose, S. L. Green, R. B. Fulton and S. L. Fernando (2019). "Integrating basophil activation tests into evaluation of perioperative anaphylaxis to neuromuscular blocking agents." Br J Anaesth 123: -.

Linauskiene, K., G. Grinceviciene, L. Malinauskiene, A. Blaziene and A. Chomiciene (2020). "Severe anaphylactic reaction to cisatracurium during anesthesia with cross-reactivity to atracurium." Open Med (Wars) 15: 384-386.

Macharadze, T., A. Davies and I. Fedor (2019). "A Well-Trained Team During Anaphylactic Shock After Rocuronium in a Patient With Aortic Stenosis: A Case Report." Front Med (Lausanne) 6: 305.

Mertes, P. M., M. C. Laxenaire and F. Alla (2003). "Anaphylactic and Anaphylactoid Reactions Occurring

during Anesthesia in France in 1999–2000." The Journal of the American Society of Anesthesiologists. 99: 536-545.

Morimoto, Y., S. Satake, A. Kamitani, M. Yamada, M. Saitou, Y. Torii, R. Shiba, C. Hadase and T. Yamamoto (2018). "Rocuronium anaphylaxis in a 7-year-old boy during the induction of anesthesia." Immunol Med 41: 85-88.

Pacifici, G. M. (2022). "Clinical Pharmacology of Rocuronium in Infants and Children." Journal of Clinical Case Reports and Studies 3: 01-07.

Petitpain, N., L. Argoullon, K. Masmoudi, S. Fedrizzi, J. Cottin, C. Latarche, P. M. Mertes, P. Gillet and C. French Network of Regional Pharmacovigilance (2018). "Neuromuscular blocking agents induced anaphylaxis: Results and trends of a French pharmacovigilance survey from 2000 to 2012." Allergy 73: 2224-2233.

Reddy, J. I., P. J. Cooke, J. M. van Schalkwyk, J. A. Hannam, P. Fitzharris and S. J. Mitchell (2015). "Anaphylaxis is more common with rocuronium and succinylcholine than with atracurium." Anesthesiology 122: 39-45.

Rose, M. A., J. Anderson, S. L. Green, J. Yun and S. L. Fernando (2018). "Morphine and pholcodine-specific IgE have limited utility in the diagnosis of anaphylaxis to benzylisoquinolines." Acta Anaesthesiol Scand 62: 628-634.

Sadleir, P. H., R. C. Clarke, D. L. Bunning and P. R. Platt (2013). "Anaphylaxis to neuromuscular blocking drugs: incidence and cross-reactivity in Western Australia from 2002 to 2011." Br J Anaesth 110: 981-987.

Sadleir, P. H. M., R. C. Clarke, C. E. Goddard, C. Day, W. Weightman, A. Middleditch and P. R. Platt (2021). "Relationship of perioperative anaphylaxis to neuromuscular blocking agents, obesity, and pholcodine consumption: a case-control study." Br J Anaesth 126: 940-948.

Takahashi, K., S. Tanaka, M. Watanabe and M. Yamakage (2019). "Rocuronium-induced anaphylaxis: a case report." JA Clin Rep 5: 81.

Takazawa, T., T. Horiuchi, K. Nagumo, Y. Sugiyama, T. Akune, Y. Amano, M. Fukuda, T. Haraguchi, C. Ishibashi, E. Kanemaru, T. Kato, K. Katoh, T. Kawano, T. Kochiyama, M. Kuri, A. Kurita, Y. Matsuoka, T. Muramatsu, M. Orihara, Y. Saito, N. Sato, T. Shiraishi, K. Suzuki, M. Takahashi, T. Takahashi, K. Tanabe, A. Tomioka, Y. Tomita, T. Tsuji, I. Watanabe, T. Yamada, N. Yoshida, M. Yamaguchi and S. Saito (2023). "The Japanese Epidemiologic Study for Perioperative Anaphylaxis, a prospective nationwide study: allergen exposure, epidemiology, and diagnosis of anaphylaxis during general anaesthesia." Br J Anaesth 131: 159-169.

Takise, Y., J. Kato, T. Suhara, T. Yamada, T. Funakoshi, H. Takahashi, M. Amagai and H. Morisaki (2020). "Life-threatening rocuronium-induced anaphylactic shock without cutaneous manifestations successfully reversed with sugammadex: a case report." JA Clin Rep 6: 95.

Toh, T. S., S. Y. Foo, W. Loh, K. W. Chong, A. En Goh, H. I. Hee and S. H. Goh (2021). "Perioperative anaphylaxis: A five-year review in a tertiary paediatric hospital." Anaesth Intensive Care 49: 44-51.